α-galactosidase a-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease

Abstract

Fabry disease is an X-linked lysosomal storage disease caused by a-galactosidaseA(a-Gal A) deficiency. Kidney and heart failure are frequent complications in adulthood and greatly contribute to patient morbidity and mortality. Because a-GalA-deficientmousemodels do not recapitulate cardiorenal findings observed in patients, a nonmouse model may be beneficial to our understanding of disease pathogenesis. In this study, we evaluated disease processes in a recently generated Fabry ratmodel.We found thatmale Fabry ratsweighed significantly less than wild-type (WT) males, whereas female Fabry rats weighed significantly more thanWT females. Whereas no difference in female survival was detected, we observed that male Fabry rats had a decreased lifespan. Skin histology revealedthat inflammationandlipoatrophymaybe chiefdiseasemediators inpatients.With respect to the kidney and heart,we found that both organs accumulate a-GalAsubstrates, including the established biomarkers, globotriaosylceramide and globotriaosylsphingosine. Longitudinal serum and urine chemistry panels demonstrated pronounced renal tubule dysfunction, which was confirmed histologically. Mitral valve thickening was observedinFabry ratsusing echocardiography.We conclude thatFabry rats recapitulate importantkidney andheart phenotypes experienced by patients and can be further used to study disease mechanisms and test therapies.